Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany German Center for Diabetes Research, Partner Düsseldorf, Germany.
German Center for Diabetes Research, Partner Düsseldorf, Germany Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.
Diabetes. 2014 Nov;63(11):3856-67. doi: 10.2337/db13-1794. Epub 2014 Jun 10.
Although insulin resistance is known to underlie type 2 diabetes, its role in the development of type 1 diabetes has been gaining increasing interest. In a model of type 1 diabetes, the nonobese diabetic (NOD) mouse, we found that insulin resistance driven by lipid- and glucose-independent mechanisms is already present in the liver of prediabetic mice. Hepatic insulin resistance is associated with a transient rise in mitochondrial respiration followed by increased production of lipid peroxides and c-Jun N-terminal kinase activity. At the onset of diabetes, increased adipose tissue lipolysis promotes myocellular diacylglycerol accumulation. This is paralleled by increased myocellular protein kinase C θ activity and serum fetuin A levels. Muscle mitochondrial oxidative capacity is unchanged at the onset but decreases at later stages of diabetes. In conclusion, hepatic and muscle insulin resistance manifest at different stages and involve distinct cellular mechanisms during the development of diabetes in the NOD mouse.
虽然已知胰岛素抵抗是 2 型糖尿病的基础，但它在 1 型糖尿病发展中的作用越来越受到关注。在 1 型糖尿病模型，非肥胖型糖尿病（NOD）小鼠中，我们发现由脂质和葡萄糖非依赖性机制驱动的胰岛素抵抗在糖尿病前期小鼠的肝脏中已经存在。肝胰岛素抵抗与线粒体呼吸的短暂增加有关，随后是脂质过氧化物的产生增加和 c-Jun N-末端激酶活性增加。在糖尿病发病时，增加的脂肪组织脂肪分解促进肌细胞二酰基甘油的积累。这与肌细胞蛋白激酶 Cθ活性和血清胎球蛋白 A 水平的增加平行。肌肉线粒体氧化能力在发病时不变，但在糖尿病后期阶段下降。总之，在 NOD 小鼠糖尿病的发展过程中，肝和肌肉胰岛素抵抗在不同阶段表现出来，并涉及不同的细胞机制。
